Bidirectional Changes in Anisotropy Are Associated with Outcomes in Mild Traumatic Brain Injury.

BACKGROUND AND PURPOSE: Mild traumatic brain injury results in a heterogeneous constellation of deficits and symptoms that persist in a subset of patients. This prospective longitudinal study identifies early diffusion tensor imaging biomarkers of mild traumatic brain injury that significantly relate to outcomes at 1 year following injury. MATERIALS AND METHODS: DTI was performed on 39 subjects with mild traumatic brain injury within 16 days of injury and 40 controls; 26 subjects with mild traumatic brain injury returned for follow-up at 1 year. We identified subject-specific regions of abnormally high and low fractional anisotropy and calculated mean fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity across all white matter voxels brain-wide and each of several white matter regions. Assessment of cognitive performance and symptom burden was performed at 1 year. RESULTS: Significant associations of brain-wide DTI measures and outcomes included the following: mean radial diffusivity and mean diffusivity with memory; and mean fractional anisotropy, radial diffusivity, and mean diffusivity with health-related quality of life. Significant differences in outcomes were found between subjects with and without abnormally high fractional anisotropy for the following white matter regions and outcome measures: left frontal lobe and left temporal lobe with attention at 1 year, left and right cerebelli with somatic postconcussion symptoms at 1 year, and right thalamus with emotional postconcussion symptoms at 1 year. CONCLUSIONS: Individualized assessment of DTI abnormalities significantly relates to long-term outcomes in mild traumatic brain injury. Abnormally high fractional anisotropy is significantly associated with better outcomes and might represent an imaging correlate of postinjury compensatory processes.

RF excitation profiles with FAIR: impact of truncation of the arterial input function on quantitative perfusion.

This study investigates the impact of imaging coil length and consequent truncation of the arterial input function on the perfusion signal contrast obtained in the flow-sensitive alternating inversion recovery (FAIR) perfusion imaging measurement. We examined the difference in perfusion contrast achieved with head, head and neck, and body imaging coils based on the hypothesis that the standard head coil provides a truncated input function compared with that provided by the body coil and that this effect will be accentuated at long inversion times. The TI-dependent cerebral response of the FAIR sequence was examined at 1.5 T by varying the TI from 200 to 3500 msec with both the head and whole body coils (n = 5) as well as using a head and neck coil (n = 3). Difference signal intensity DeltaM and quantitative cerebral blood flow (CBF) were plotted against TI for each coil configuration. Despite a lower signal-to-noise ratio, relative CBF was significantly greater when measured with the body or head and neck coil compared with the standard head coil for longer inversion times (two-way ANOVA, P < or = 0.002). This effect is attributed to truncation of the arterial input function of labeled water by the standard head coil and the resultant inflow of unlabeled spins to the image slice during control image acquisition, resulting in overestimation of CBF. The results support the conclusion that the arterial input function depends on the anatomic extent of the inversion pulse in FAIR, particularly at longer mixing times (TI > 1200 msec at 1.5 T). Use of a head and neck coil ensures adequate inversion while preserving SNR that is lost in the body coil.

Effect of leukocyte-endothelial adhesion antagonism on neutrophil migration and neurologic outcome after cortical trauma.

BACKGROUND: Administration of anti-CD11B, a monoclonal antibody directed against the leukocyte adhesion molecule CD11B, results in decreased neutrophil infiltration into injured tissue after experimental ischemia. We determined the effect of anti-CD11B administration on neutrophil migration and neurologic functioning after experimental cortical trauma. METHODS: Injuries were produced by a pneumatic impactor. Treatment animals received anti-CD11B after injury. Neurologic functioning was quantitated at 1, 12, and 24 hours after injury. Neutrophil migration was assessed with the myeloperoxidase assay. RESULTS: Neutrophil influx was increased in injured cortex after trauma. Anti-CD11B significantly reduced neutrophil influx. There was no significant improvement in neurologic functioning after MAb administration. CONCLUSIONS: These results show there is marked neutrophil response to injury as produced with the pneumatic contusion model. This migration may be significantly attenuated by administration of a anti-CD11B.

Rapid and continuous monitoring of cerebral perfusion by magnetic resonance line scan assessment with arterial spin tagging.

A new approach is presented for rapid and continuous monitoring of cerebral perfusion which is based upon line-scan MR column imaging with arterial spin tagging (AST) of endogenous water. Spin tagging of arterial water protons is accomplished using adiabatic fast passage inversion, followed by acquisition of the perfusion sensitive MR signal from a column placed at the desired level through the brain using line scan localization techniques. A perfusion sensitive line scan is followed by a non-perfusion sensitive line scan, and perfusion is calculated pixel-by-pixel from the intensity difference of the two lines. Continuous perfusion measurements are reported with temporal resolution of 10 s in pixels of volume 0.027 cm3 or less. Examples of the methodology are given during hypercapnic challenge induced with carbon dioxide, and during an ischemic event induced by reversible middle cerebral artery occlusion. The method is also used to characterize the signal response as a function of arterial inversion time and post inversion acquisition delay. These methods permit rapid and continuous monitoring of cerebral perfusion with high spatial resolution, and can be interleaved with MR measurements of diffusion and T1 to follow the progression of cerebral events during physiological or pharmacological intervention.

Perfusion imaging using FOCI RF pulses.

Pulsed arterial spin-tagging techniques for perfusion measurements (e.g., echo planar MR imaging and signal targeting with alternating radiofrequency (EPISTAR), flow-sensitive alternating inversion recovery (FAIR), quantitative imaging of perfusion using a single subtraction (QUIPPS), uninverted FAIR (UNFAIR)) generally use hyperbolic secant (HS) pulses for spin inversion. The performance of these techniques depends on the inversion efficiency, as well as the sharpness of the slice profiles. Frequency offset corrected inversion (FOCI) pulses, a recently proposed HS variant, can provide slice profiles with edges that can be up to 10 times sharper than those obtained with conventional HS pulses. In this communication, the implementation and application of the C-shape FOCI pulse for perfusion imaging in rat brain with the FAIR technique is summarized. Despite providing a more rectangular slice profile than a conventional HS pulse, it is demonstrated both theoretically and experimentally that the FAIR perfusion signal is not increased by using a FOCI tagging pulse. However, the use of a FOCI inversion pulse is shown to significantly minimize static signal subtraction errors that are common with conventional HS pulses. Finally, the suitability of the pulse for perfusion studies is demonstrated, in vivo, on rat brain.

Neuropsychological dose effects of a freon, trifluoromethane (FC-23), compared to N2O.

Animal studies show FC-23 to be a promising magnetic resonance imaging indicator of regional cerebral blood flow. In a Phase 1, dose ranging (investigative new drug) study, neuropsychological (NP) tests, subjective ratings, and intensive physiological monitoring were used to determine the maximum tolerated concentration of FC-23 for human application. Five normal healthy male volunteers were exposed to concentrations of FC-23 between 10% and 60% [randomly interleaved with exposures to both room air and 40% nitrous oxide (N2O)] in a within-subjects, double-blind design. Analyses of individual cases and ranked group data showed that individuals tolerated the 30% concentration of FC-23 according to established criteria. Planned comparisons indicated that inhalation of FC-23 produced smaller NP changes and fewer negative symptoms than 40% N2O but poorer NP performance and more negative symptoms than room air. This study indicated that FC-23 is not inert and that humans do not tolerate concentrations suitable for current MRI technology. NP and subjective data assisted in characterizing the sedative effect of FC-23.

Diastolic shape of the right ventricle of the heart.

BACKGROUND: Knowledge of right ventricular (RV) shape is important to the understanding of RV mechanical function and for the improvement of clinically important RV volume estimation techniques. Refinements to the simplest conceptions of RV shape are presented statistically here, based on a quantitative analysis of three-dimensional magnetic resonance (MR) images of excised lamb hearts. METHODS: The passive shape of the heart in six freshly excised lamb hearts was studied with MR imaging with independent passive pressurization of both ventricles. Global features of shape were assessed, including measurement of short-axis, cross-sectional shape parameters associated with the pinched-arc model. RESULTS: The slice-area x apex-base length was found to be highly correlated with the volume of the RV, with little sensitivity to the degree of filling of the ventricle or to the exact slice chosen (r = 0.987; n = 22 from five hearts). The RV was shown to follow a clockwise helical path around the left ventricle of 47 +/- 17 degrees, below the outflow tract, as seen from the apical view, progressing from the apex to the base. Based on the pinched-arc model, the anterior arc is shallower than the posterior arc, with a larger radius of curvature and a smaller angle between the arc and the septal axis. As the RV is passively filled, opposite changes in shape occur between the anterior and posterior regions tending to equalize their shapes. CONCLUSIONS: A high degree of regularity of shape does exist in the RV and, thus, can be characterized effectively in terms of a representative cross-sectional shape and in terms of the changes in that shape proceeding from the base to the apex.

The application of diffusion-weighted line-scanning for the rapid assessment of water ADC changes in stroke at high magnetic fields.

Rapid changes in the apparent diffusion coefficient of water following brain ischemia have been extensively studied using echo planar diffusion imaging at low fields (2.0 T). There is a desire to perform these studies at higher fields (> 3.0 T) where the benefits of improved signal-to-noise can be exploited. Unfortunately, EPI diffusion is technically difficult to implement at high fields because of large magnetic susceptibility effects. This article demonstrates the feasibility of employing a line-scan diffusion protocol for ADCw measurements in stroke. The technique was applied on a 4.0 T system to monitor the decline in ADCw following the induction of focal cerebral ischemia in rat. ADCw data were acquired every 15 s with 10 b-values or every 22.5 s with 15 b-values, with a cubic spatial resolution of 1.5 mm. The results demonstrate that estimates of ADCw can be acquired with coefficients of variation under 3.0%, and with a combination of spatial and temporal resolution comparable to that previously reported for EPI.

Perfusion imaging by un-inverted flow-sensitive alternating inversion recovery (UNFAIR).

A new pulse sequence for estimating cerebral blood flow called UNFAIR, which uses a combination of sequential hyperbolic secant preparatory pulses, is introduced. This sequence is based on the same generalized conditions as previously introduced inversion recovery techniques except that the spins in the image slice of interest always have +z magnetization and the in-flowing spins are alternately inverted and uninverted. CBF-weighted images of rat brain under conditions of normocpnia and hypercapnia are presented and demonstrate the expected CBF response. A model describing the signal response to this pulse sequence is also presented and compared with in-vivo data acquired from gray and white matter.

Effect of L-NAME on pressure-flow relationships in isolated rabbit lungs: role of red blood cells.

Nitric oxide (NO) is produced by and relaxes pulmonary arteries and veins; however, a role for NO as a participant in the control of pulmonary vascular resistance (PVR) remains to be defined. Here we investigated the hypothesis that for NO to serve as a determinant of PVR in the rabbit requires the presence of blood. In isolated blood-perfused rabbit lungs, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) increased PVR and the slope of the pressure-flow relationship. These effects of L-NAME were prevented by pretreatment with L-arginine. In contrast, in lungs perfused with a physiological salt solution, L-NAME had no effect on PVR or the pressure-flow relationship. The addition of washed red blood cells (RBCs) to physiological salt solution, but not the addition of plasma and platelets, restored the response to L-NAME. This effect of RBCs was not reproduced by increasing perfusate viscosity with dextran. These results suggest that, in the rabbit lung, NO is a determinant of PVR in the presence of blood. Moreover, that aspect of blood that permits the generation of NO appears to be related to the RBC and not to perfusate viscosity.

Neurobehavioral and physiologic effects of trifluoromethane in humans.

Nuclear magnetic resonance (NMR) imaging shows promise in the measurement of human cerebral blood flow (CBF) in that nonradioactive indicators may be used. Our earlier investigations with trifluoromethane (FC-23) gas have shown that this compound can be used to safely and effectively measure CBF in anesthetized animal models. In this Phase I dose-escalation study we set out to determine the maximal tolerated concentration (MTC) of FC-23 in normal healthy male volunteers and to assess its feasibility as an NMR indicator. Five subjects were exposed in a blinded fashion to escalating concentrations of FC-23 between 10% and 60%, randomly interleaved with exposures to both room air and 40% nitrous oxide. On each study day, the subjects breathed the test gas for eight pulses of 3 min each with 2-min clearance periods between the pulses. The subjects underwent intensive physiologic and neurobehavioral monitoring throughout the study period. The first subject experienced an anesthetic response to 60% FC-23, and the second subject experienced "discomfort" and requested discontinuation at the initiation of 40% FC-23. The MTC was subsequently determined to be 30% FC-23 (all subjects tolerated the gas), although a small (37.6 vs. 40.5) but statistically significant retention of carbon dioxide was found (p = .003). When one subject received 30% FC-23 during an NMR imaging study, a pronounced anesthetic effect with intolerable hyperacusis was demonstrated. Human studies of FC-23 have been discontinued in our laboratory.

Endothelium-dependent relaxation to arachidonic acid in porcine coronary artery: is there a fourth pathway?

Endothelium-dependent relaxations to bradykinin (BK) in U46619-contracted, indomethacin (INDO)-treated porcine coronary artery (PCA) rings are modestly attenuated by the nitric oxide (NO) synthase inhibitor, N omega-nitro-l-arginine methyl ester (L-NAME); whereas, when contracted with KCl, L-NAME abolishes BK relaxations. In contrast, endothelium-dependent arachidonic acid (AA) relaxations of U46619-contracted, INDO-treated PCA rings are not affected by L-NAME. AA does not relax KCl-contracted rings. Since BK is known to release AA, we postulated that the non-NO component of BK relaxation of the PCA is mediated by AA or an AA metabolite. Changes in tension of PCA rings to BK and AA were determined in the presence and absence of phospholipase (PLA), cyclooxygenase (CO), lipoxygenase (LO) and cytochrome P-450 (cP450) inhibitors. Responses to BK were attenuated by PLA inhibitors. No other inhibitors, however, eliminated responses to either BK or AA. The results suggest that relaxation to BK in PCA rings requires PLA activity, but relaxation to AA is independent of PLA, CO, LO or cP450 activity. We conclude that relaxation to BK and AA in the PCA is mediated by a product of an unidentified pathway of AA metabolism or by an unknown second messenger system resident within the endothelium and responsive to AA.

Inhibition of nitric oxide synthesis results in a selective increase in arterial resistance in rabbit lungs.

Endogenous nitric oxide (NO) opposes the vasoconstriction that occurs when lungs are ventilated with a hypoxic gas mixture. However, the contribution of NO to pulmonary vascular resistance when alveolar gas tension is not reduced remains to be defined. Here, we investigated the hypothesis that endogenous NO is a determinant of pulmonary vascular resistance in isolated perfused rabbit lungs ventilated with a normoxic gas mixture. Moreover, we wished to establish that, as flow rate increases, the contribution of NO to vascular resistance increases. In addition, we examined the contribution of NO to the longitudinal distribution of pulmonary vascular resistance. Pressure-flow curves were generated in isolated blood perfused rabbit lungs by varying flow rate from 50 ml/min to 300 ml/min in the presence and absence of the cyclooxygenase inhibitor, indomethacin (100 microM) and the inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM). Indomethacin did not alter total pulmonary vascular resistance or the longitudinal distribution of resistance. In contrast, L-NAME administration resulted in significant, flow-related increases in total vascular resistance, i.e., after L-NAME, as flow rate increased, the increment in resistance increased. L-NAME-induced increases in total pulmonary vascular resistance were the result of flow-related increases in the arterial component of vascular resistance. These results provide support for the hypothesis that NO is an important determinant of pulmonary vascular resistance in the rabbit and that the major site of NO activity resides in the arterial side of that circulation.

Causes of differential cardiovascular sensitivity to cocaine. II: Sympathetic, metabolic and cardiac effects.

Cocaine elicits a decrease in cardiac output only in a subset of rats; this reduction is mitigated by prazosin, nifedipine, verapamil or pentolinium and exacerbated by propranolol. In the present study, we examined other correlates or causes of differential responsiveness, including differences in cocaine metabolism, sympathetic nerve responses, catecholamine sensitivity and direct cardiac actions. Arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, yet cardiac output responses, as determined by pulsed Doppler flowmetry, varied widely. Cocaine elicited a mean maximal decrease of more than 15% in 17 rats designated responders, whereas the remaining rats (n = 19) were classified as nonresponders. Maximal heart rate responses to phenylephrine- and nitroprusside-induced pressor and depressor stimuli were greater in responders than in nonresponders. Phenylephrine also elicited significantly greater decreases in cardiac output and smaller increases in stroke volume in responders. After we determined the responses to cocaine in conscious rats, animals were anesthetized with alpha-chloralose for renal nerve recording. Several rats (14 of 21 tested) demonstrated an initial brief (2-12 sec) increase in sympathetic activity, whereas all rats subsequently had a delayed sympathoinhibition. Responders were more likely to have sympathoexcitation compared with nonresponders and had an enhanced initial pressor response and a smaller decrease in heart rate. There were no differences in plasma or cerebrospinal fluid levels of cocaine or its metabolites, benzoylecgonine and ecgonine methyl ester. Intravenous benzoylecgonine elicited a pressor response and bradycardia in conscious rats. Finally, there were no differences in contractile, electrocardiographic or coronary vascular responses to cocaine in isolated, perfused hearts from responders and nonresponders. These results suggest that the differential cardiovascular responsiveness to cocaine in rats is mediated, at least in part, by central sympathoexcitation and not by differences in cocaine metabolism or in direct cardiac responsiveness to cocaine.

Evaluation of the acute cardiac and central nervous system effects of the fluorocarbon trifluoromethane in baboons.

The gaseous fluorocarbon trifluoromethane has recently been investigated for its potential as an in vivo gaseous indicator for nuclear magnetic resonance studies of brain perfusion. Trifluoromethane may also have significant value as a replacement for chlorofluorocarbon fire retardants. Because of possible species-specific cardiotoxic and anesthetic properties, the toxicological evaluation of trifluoromethane in primates (Papio anubis) is necessary prior to its evaluation in humans. We report the acute cardiac and central nervous system effects of trifluoromethane in eight anesthetized baboons. A dose-response effect was established for respiratory rate, electroencephalogram, and cardiac sinus rate, which exhibited a stepwise decrease from 10% trifluoromethane. No spontaneous arrhythmias were noted, and arterial blood pressure remained unchanged at any inspired level. Intravenous epinephrine infusions (1 microgram/kg) induced transient cardiac arrhythmia in 1 animal only at 70% FC-23 (v/v) trifluoromethane. Trifluoromethane appears to induce mild dose-related physiological changes at inspired levels of 30% or more, indicative of an anesthetic effect. These data suggest that trifluoromethane may be safe to use in humans, without significant adverse acute effects, at an inspired level of 30%.

Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid.

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KCl, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinin-induced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 mumol/L) were moderately attenuated by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 mumol/L), whereas when precontracted with KCl, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings precontracted with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KCl. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 mumol/L) and 4-bromophenacyl bromide (10 mumol/L) attenuated bradykinin- but not AA-induced relaxations. Inhibitors of both lipoxygenase (BW 755c [100 mumol/L] and nafazatrom [20 mumol/L]) and cytochrome P-450 (proadifen [10 mumol/L] and clotrimazole [10 mumol/L]) pathways did not eliminate bradykinin- or AA-induced relaxations, although clotrimazole partially attenuated AA-induced relaxations. These findings suggest that bradykinin-induced relaxation of PCA rings is mediated by AA through a mechanism that is not dependent on cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways.

Causes of differential cardiovascular sensitivity to cocaine. I: Studies in conscious rats.

Cocaine produces apparent myocardial ischemia in some individuals without deleterious effects in others. The authors identified a subset of rats in which cocaine produces a decrease in cardiac output and an increase in cardiomyopathies. In the present study, several potential causes of this differential responsiveness were examined in conscious rats instrumented for cardiac output determination by using pulsed Doppler flowmetry. Although arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, cardiac output responses varied widely. Specifically, in 17 of 36 rats, cocaine elicited a maximum decrease of greater than 15% that was relatively consistent with repeated trials. These rats were designated responders, whereas the remaining rats with little change or an increase in cardiac output were classified as nonresponders. Pentolinium (7.5 mg/kg) or adrenal demedullation reduced the peak cardiac output responses in both groups such that there was no longer a difference between responders and nonresponders. Prazosin (0.1 mg/kg) reduced the cocaine-induced pressor responses in all rats and selectively reduced the decrease in cardiac output in responders. Propranolol (1 mg/kg) reduced the peak pressor response but enhanced the decrease in cardiac output in responders. Neither indomethacin (5 mg/kg) or heparin (300 units) pretreatment altered the cocaine-induced cardiac output or peripheral vascular effects in either responders or nonresponders. Amphetamine (1 mg/kg) elicited smaller pressor responses but still evoked a net decrease in cardiac output in responders.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonadrenergic mechanisms of cocaine-induced regional vascular responses in rats.

The pressor response to cocaine is a consequence of mesenteric vasoconstriction and hindquarters vasodilation as a result of activation of alpha 1- and beta-adrenergic receptors, respectively. In the present study, evidence for additional, nonadrenergic effects of cocaine-induced changes in regional blood flow was obtained using pulsed Doppler flowmetry in conscious rats. Cocaine produced dose-dependent initial peaks (within 1 min) in mean arterial pressure concomitant with an increase in hindquarters and mesenteric vascular resistance. The sustained, modest pressor response was associated with hindquarters vasodilation and bradycardia. The cocaine-induced vasodilation was enhanced by pretreatment with indomethacin (5 mg/kg), prevented by ibuprofen (12.5 mg/kg) or 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C, 10.5 mg/kg) pretreatment, and unaffected by meclofenamate administration (2.5 mg/kg). Equipotent local anesthetic doses of procaine produced equivalent hindquarters vasodilator responses and more modest pressor responses. Dial-urethane anesthesia did not affect hindquarters vasodilation in response to cocaine or procaine but did reduce the mesenteric vasoconstrictor and pressor responses. These data demonstrate that the cocaine-induced hindquarters vasodilation is not mediated solely by beta-adrenergic receptors but is also dependent upon eicosanoids. Furthermore, the cocaine-induced vasodilation may be due, in part, to a direct local anesthetic effect but is not dependent upon a locomotor or behavioral stress induced increase in blood flow.

Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats.

Cocaine use has been associated with profound functional and pathological myocardial responses in otherwise asymptomatic humans, yet a number of individuals appear to tolerate large doses of the drug. This study was designed to determine whether there is a relationship between the differential effects of cocaine administration on cardiovascular responses and on the development of cardiomyopathies in rats. After instrumentation for determination of cardiac output, conscious, freely moving rats were treated with cocaine (5 mg/kg) or saline intravenously twice daily for 14 days before removing the myocardium for analysis. Although most cardiovascular responses were similar, cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others showed little change or an increase. While little change was evident at low magnification, electron microscopy revealed diffusely distributed myocardial lesions including focally dilated sarcoplasmic reticulum and myofibrillar derangement, early signs of mitochondrial alterations, and foci of myocardial fibrosis. The incidence of these alterations was greater in rats with a decrease in cardiac output. We also observed these lesions in a subset of rats treated with cocaine without cardiac output instrumentation. These data represent the first evidence that there is a relationship between cocaine-induced functional and pathological alterations and that rats, like humans, may be differentially sensitive to these effects.

Stress and cocaine elicit similar cardiac output responses in individual rats.

Cocaine use and behavioral stress elicit variable cardiovascular responses in individuals. In the present study, we examined the effects of cocaine or stress on arterial pressure, heart rate, and cardiac output in conscious rats. Rats were instrumented for determination of ascending aortic blood flow as an index of cardiac output using pulsed Doppler flow-metry. Cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others had increases. In contrast, the pressor and heart rate responses were similar in these two groups of animals. Air jet stress also elicited a decrease in cardiac output only in a subset of conscious rats, yet produced equivalent pressor responses in all rats. Cardiac output responses to cocaine and air jet stress were closely correlated in individual rats, indicating that these stimuli evoke similar hemodynamic responses in individual rats. These observations suggest that the rat may provide a model for understanding differential cardiovascular sensitivity to cocaine and/or stress in humans.